The overall objective is to examine biochemical mechanisms of long-term depression of GAGAA receptor-mediated responses in CA1 pyramidal cells of the guinea-pig hippocampus, GABAA responses will be examined during: I.1. Internal perfusion of active phosphatase-2B (PP-2B). I.2. [Ca2plus]i - induced activation of calpain and PP-2B. Hypothesis: calpain induces active PP-2B by limited proteolisys. II.1. Internal perfusion of active calmodulin kinase II (CaMKII). II.2 [Ca2plus]i - induced activation of PP-2B and CaMKII. Hypothesis: PP-2B activation results in formation of active CaMKII. III.1 Internal perfusion of active protein kinase C (PKC). III.2 [Ca2plus]i - induced activation of calpain and PCK. Hypothesis: calpain mediates formation of active PCK (PKCM) via limited proteolysis. Whole-cell clamp recordings will be performed in isolated cells and cells in the hippocampal slice. Intracellular application active enzymes or elevation of [Ca2plus]i will be achieved by internal perfusion. To achieve the isolated activation of targeted enzymes by [Ca2plus]i (e.g. calpain and PP-2B in 1.2), specific inhibitors of other [Ca2plus]i - activated enzymes will be used (e.g., inhibitors for CaMKII or PKC in 1.2). Impairment of GABAA -mediated inhibition results in profound increases of excitability in situ. Such mechanism may be important in physiological (e.g. learning) and pathological (e.g. epilepsy) states of the cortex.